α, β-unsaturated sulfones for treating proliferative disorders

ABSTRACT

alpha, beta-Unsaturated sulfones of the following formulae are provided, which are useful as antiproliferative agents, including, for example, anticancer agents:

CROSS-REFERENCE TO RELATED APPLICATIONS

The benefit of the filing dates of provisional application Serial No.60/197,368, filed Apr. 14, 2000, is claimed pursuant to 35 U.S.C.1119(e). The entire disclosures of the aforesaid provisional applicationis incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to compositions and methods for the treatment ofcancer and other proliferative disorders.

BACKGROUND OF THE INVENTION

Extracellular signals received at transmembrane receptors are relayedinto the cells by the signal transduction pathways (Pelech et al.,Science 257:1335 (1992)) which have been implicated in a wide array ofphysiological processes such as induction of cell proliferation,differentiation or apoptosis (Davis et al., J. Biol. Chem. 268:14553(1993)). The Mitogen Activated Protein Kinase (MAPK) cascade is a majorsignaling system by which cells transduce extracellular cues intointracellular responses (Nishida et al., Trends Biochem. Sci. 18:128(1993); Blumer et al., Trends Biochem. Sci. 19:236 (1994)). Many stepsof this cascade are conserved, and homologous for MAP kinases have beendiscovered in different species.

In mammalian cells, the Extracellular-Signal-Regulated Kinases (ERKs),ERK-1 and ERK-2 are the archetypal and best-studied members of the MAPKfamily, which all have the unique feature of being activated byphosphorylation on threonine and tyrosine residues by an upstream dualspecificity kinase (Posada et al., Science 255:212 (1992); Biggs III etal., Proc. Natl. Acad. Sci. USA 89:6295 (1992); Garner et al., GenesDev. 6:1280 (1992)).

Recent studies have identified an additional subgroup of MAPKs, known asc-Jun NH2-terminal kinases 1 and 2 (JNK-1 and JNK-2), that havedifferent substrate specificities and are regulated by different stimuli(Hibi et al., Genes Dev. 7:2135 (1993)). JNKs are members of the classof stress-activated protein kinases (SPKs). JNKs have been shown to beactivated by treatment of cells with UV radiation, pro-inflammatorycytokines and environmental stress (Derijard et al., Cell 1025 (1994)).The activated JNK binds to the amino terminus of the c-Jun protein andincreases the protein's transcriptional activity by phosphorylating itat ser63 and ser73 (Adler et al., Proc. Natl. Acad. Sci. USA 89:5341(1992); Kwok et al., Nature 370:223 (1994)).

Analysis of the deduced primary sequence of the JNKs indicates that theyare distantly related to ERKs (Davis, Trends Biochem. Sci. 19:470(1994)). Both ERKs and JNKs are phosphorylated on Tyr and Thr inresponse to external stimuli resulting in their activation (Davis,Trends Biochem. Sci. 19:470 (1994)). The phosphorylation (Thr and Tyr)sites, which play a critical role in their activation are conservedbetween ERKs and JNKs (Davis, Trends Biochem. Sci. 19:470 (1994)).However, these sites of phosphorylation are located within distinct dualphosphorylation motifs: Thr-Pro-Tyr (JNK) and Thr-Glu-Tyr (ERK).Phosphorylation of MAPKs and JNKs by an external signal often involvesthe activation of protein tyrosine kinases (PTKs) (Gille et al., Nature358:414 (1992)), which constitute a large family of proteinsencompassing several growth factor receptors and other signaltransducing molecules.

Protein tyrosine kinases are enzymes which catalyze a well definedchemical reaction: the phosphorylation of a tyrosine residue (Hunter etal., Annu Rev Biochem 54:897 (1985)). Receptor tyrosine kinases inparticular are attractive targets for drug design since blockers for thesubstrate domain of these kinases is likely to yield an effective andselective antiproliferative agent. The potential use of protein tyrosinekinase blockers as antiproliferative agents was recognized as early as1981, when quercetin was suggested as a PTK blocker (Graziani et al.,Eur. J. Biochem. 135:583-589 (1983)).

The best understood MAPK pathway involves extracellular signal-regulatedkinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijnet al., Trends Biochem. Sci. 20, 18 (1995)). Once this pathway isactivated by different stimuli, MAPK phosphorylates a variety ofproteins including several transcription factors which translocate intothe nucleus and activate gene transcription. Negative regulation of thispathway could arrest the cascade of these events.

What are needed are new anticancer chemotherapeutic agents which targetreceptor tyrosine kinases and which arrest the Ras/Raf/MEK/ERK kinasecascade. Oncoproteins in general, and signal transducing proteins inparticular, are likely to be more selective targets for chemotherapybecause they represent a subclass of proteins whose activities areessential for cell proliferation, and because their activities aregreatly amplified in proliferative diseases.

What is also needed are new cell antiproliferative agents, andanticancer therapeutics in particular, which are highly selective in thekilling of proliferating cells such as tumor cells, but not normalcells.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds, compositions andmethods for the treatment of cancer and other proliferative diseases.The biologically active compounds are in the form of certain sulfonecompounds.

It is an object of the invention to provide compounds which are highlyselective in killing tumor cells but not normal cells.

According to one embodiment of the invention, novel compounds areprovided according to formula I:

wherein:

Q₁ is selected from the group consisting of

(a) a phenyl radical according to formula II

wherein

R₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl;

(b) an aromatic radical selected from the group consisting of1-naphthyl, 2-naphthyl and 9-anthryl; and

(c) an aromatic radical according to formula III

wherein

n₁ is 1 or 2,

Y₁ and Y₂ are independently selected from the group consisting ofhydrogen, halogen, and nitro, and

X₁ is selected from the group consisting of oxygen, nitrogen, sulfur and

and

Q₂ is selected from the group consisting of

(d) a phenyl radical according to formula II

wherein

R₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl;

(e) an aromatic radical selected from the group consisting of1-naphthyl, 2-naphthyl and 9-anthryl;

(f) an aromatic radical according to formula IV

wherein

n₂ is 1 or 2,

Y₃ and Y₄ are independently selected from the group consisting ofhydrogen, halogen, and nitro, and

X₂, X₃ and X₄ are independently selected from the group consisting ofcarbon, oxygen, nitrogen, sulfur and

provided that not all of X₂, X₃ and X₄ may be carbon; and

(g) 1-piperazinyl;

provided that at least one of Q₁ or Q₂ is other than a phenyl radicalaccording to formula II.;

or a pharmaceutically acceptable salt thereof.

According to another embodiment of the invention, novel compounds of theZ-configuration are provided according to formula V:

wherein:

X is sulfur or oxygen; and Y_(a) and Y_(b) are independently selectedfrom the group consisting of hydrogen, halogen, and nitro; and R₁through R₅ are defined as above;

or a pharmaceutically acceptable salt thereof.

According to other embodiments, processes for preparing compoundsaccording to the present invention are provided. In one such embodiment,a compound of formula I is prepared by condensing a compound of theformula Ia

with a compound of the formula

where Q₁ and Q₂ are defined as above for formula I.

The formula Ia compound may be prepared, for example, by reacting sodiumglycollate with a compound of the formula Q₁CH₂Cl to form a thioaceticcompound of the formula

which is then oxidized to form a compound of formula 1a, wherein Q₁ isdefined as above.

Alternatively, the thioacetic acid compound Q₁CH₂SCH₂COOH is prepared byreacting a compound of the formula HSCH₂COOR, where R is C1-C6 alkyl,with the aforementioned Q₁CH₂—Cl compound to form a compound of theformula:

wherein R is C1-C6 alkyl, which is then converted to the correspondingthioacetic acid compound by alkaline or acid hydrolysis.

A process for preparing compounds according to formula V is alsoprovided. A compound of the of the formula

wherein Y_(b), Y_(a) and X are defined as above, is reacted with acompound of the formula

where R₁ to R₅ are defined above, to form a sulfide compound of formulaVa:

The sulfide compound is then oxidized to form a sulfone compoundaccording to formula V.

The term “alkyl”, by itself or as part of another substituent means,unless otherwise stated, a straight or branched chain hydrocarbonradical, including di- and multi-radicals, having the number of carbonatoms designated (i.e. C1-C6 means one to six carbons) and includesstraight or branched chain groups. Most preferred is C1-C3 alkyl,particularly ethyl and methyl.

The term “alkoxy” employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group having the designatednumber of carbon atoms, as defined above, connected to the rest of themolecule via an oxygen atom, such as, for example, methoxy, ethoxy,1-propoxy, 2-propoxy and the higher homologs and isomers. Preferred areC1-C3 alkoxy, particularly ethoxy and methoxy.

By “halogen” is meant fluorine, chlorine, bromine or iodine.

By “substituted” means that an atom or group of atoms has replacedhydrogen as the substituent attached to another group.

A pharmaceutical composition is also provided comprising apharmaceutically acceptable carrier and one or more compounds of formulaI or formula V above, or a pharmaceutically acceptable salt thereof.

According to another embodiment of the invention, a method of treatingan individual for a proliferative disorder, particularly cancer, isprovided, comprising administering to said individual an effectiveamount of a compound according to formulae I or V, or a pharmaceuticallyacceptable salt thereof, alone or in combination with a pharmaceuticallyacceptable carrier.

In another embodiment of the invention, a method of inhibiting growth oftumor cells in an individual afflicted with cancer is providedcomprising administering to said individual an effective amount of acompound according to formulae I or V, or a pharmaceutically acceptablesalt thereof, alone or in combination with a pharmaceutically acceptablecarrier.

In another embodiment, a method of inducing apoptosis of cancer cells,more preferably tumor cells, in an individual afflicted with cancer isprovided, comprising administering to said individual an effectiveamount of a compound according to formulae I or V, or a pharmaceuticallyacceptable salt thereof, alone or in combination with a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, certain α,β-unsaturated sulfonesselectively kill various tumor cell types without killing normal cells.The sulfones of the present invention are characterized by cis-transisomerism resulting from the presence of a double bond. The compoundsare named according to the Cahn-Ingold-Prelog system, the IUPAC 1974Recommendations, Section E: Stereochemistry, in Nomenclature of OrganicChemistry, John Wiley & Sons, Inc., New York, N.Y., 4^(th) ed., 1992, p.127-138. Stearic relations around a double bond are designated as “Z” or“E”. Both configurations are included in the scope of the presentinvention.

According to one embodiment of the invention, the compound is accordingto formula I and has the E-configuration as shown in formula I. Thecompounds of formula I are characterized by the presence of two ringsystems Q₁ and Q₂, at least one of which comprises a heterocyclic ormulticyclic system. The other ring system, if not a heterocyclic ormulticyclic system, comprises a substituted or unsubstituted phenylradical according to formula II, above.

The ring systems Q₁ and Q₂ are optionally substituted. By “substituted”means that an atom or group of atoms has replaced hydrogen as thesubstituent attached to a ring carbon atom.

Any degree of substitution is possible on the phenyl ring of formula II.The substituents to replace hydrogen in the phenyl ring of formula IIare selected from the group consisting of halogen, C1-C6 alkyl, C1-C6alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxyand trifluoroalkoxy. By “halogen” is meant fluorine, chlorine, bromineor iodine. According to preferred embodiments, the substituents on thephenyl ring of formula II are selected from the group consisting ofhydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy and trifluoromethyl.

Where a substituent is or contains an alkyl or alkoxy group, the carbonchain may be branched or straight, with straight being preferred.Preferably, the alkyl and alkoxy groups comprise C1-C3 alkyl and C1-C3alkoxy, most preferably methyl and methoxy. The same preference holdstrue for the carbon chain in C1-C6 trifluoroalkoxy groups.

The phenyl ring may be up to penta-substituted, as shown in formula II.The pattern of multiple substitution with respect to the position of thephenyl ring of formula II may comprise any pattern of substitution. Forexample, tri-substitution may comprise substitution at positions 2, 3and 4, positions 2, 4 and 5, or positions 2, 4 and 6, for example.Likewise, the pattern of tetra-substitution may comprise, for example,substitution at positions 2, 3, 4 and 5, or positions 2, 3, 5 and 6.

According to certain embodiments, the phenyl ring of formula II istri-substituted, that is, only two of R₁ through R₅ are hydrogen.Representative combinations of substituents are set forth in Table 1:

TABLE 1 Tri-Substitution a halogen halogen halogen b halogen halogenC1-C6 alkyl c halogen halogen C1-C6 alkoxy d halogen halogen nitro ehalogen halogen carboxyl f halogen C1-C6 alkyl C1-C6 alkyl g halogenC1-C6 alkoxy C1-C6 alkoxy h C1-C6 alkyl C1-C6 alkyl C1-C6 alkyl i C1-C6alkoxy C1-C6 alkoxy C1-C6 alkoxy j C1-C6 alkyl C1-C6 alkyl nitro k C1-C6alkoxy C1-C6 alkoxy nitro

According to certain other embodiments, the phenyl ring of formula II istetra-substituted, that is, only one of R₁ through R₅ is hydrogen.Representative combinations of substituents are set forth in Table 2:

TABLE 2 Tetra-Substitution a halogen halogen halogen halogen b halogenhalogen halogen C1-C6 alkyl c halogen halogen halogen C1-C6 alkoxy dhalogen halogen halogen nitro e halogen halogen C1-C6 alkyl C1-C6 alkylf halogen halogen C1-C6 alkoxy C1-C6 alkoxy g C1-C6 alkyl C1-C6 alkylC1-C6 alkyl nitro h C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkoxy nitro

According to other embodiments, the phenyl ring of formula II ispenta-substituted, preferably with halogen, most preferably with thesame halogen.

Where the phenyl ring is mono-substituted (only one of R₁-R₅ is otherthan hydrogen), the non-hydrogen substituent is preferably located atthe 2- or 4-position (R₁ or R₃ is other than hydrogen). Where the ringis di-substituted (two of R₁-R₅ are other than hydrogen), thenon-hydrogen substituents are preferably located at the 2- and4-positions (R₁ and R₃ are other than hydrogen), or the 3- and4-positions (R₂ and R₃ are other than hydrogen).

According to certain preferred embodiments, the 4-position of the phenylring of formula II is substituted, that is, R₃ is other than hydrogen.Preferably, R₃ is halogen or C1-C6 alkoxy in these embodiments.According to one preferred embodiment, R₁ is hydrogen or halogen; R₃ ishalogen, C1-C3 alkoxy or trifluoromethyl; and R₂, R₄ and R₅ arehydrogen.

Where Q₁ of formula I is the 5- or 6-member aromatic heterocyclicradical of formula III, preferred radicals include 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-thienyl-1,1-dioxide, 3-thienyl-1,1-dioxide,2-pyridyl and 3-pyridyl. The aforesaid heterocyclic radicals may beoptionally mono- or di-substituted with halogen or nitro. Where Q₂ offormula I is the 5- or 6-member aromatic heterocyclic radical of formulaIV, preferred radicals include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-thienyl-1,1-dioxide, 3-thienyl-1,1-dioxide, 2-thiazolyl, 2-pyrrolyl,2-pyridyl, 3-pyridyl and 4-pyridyl. The aforesaid heterocyclic radicalsmay be optionally mono- or di-substituted with halogen or nitro.

According to another embodiment of the invention, the α,β-unsaturatedsulfone compound is of the Z-configuration and has the structure offormula V. The heterocyclic ring in formula V may be optionally mono- ordi-substituted with halogen or nitro. Preferred heterocyclic radicalsinclude unsubstituted 2-furyl, 3-furyl, 2-thienyl and 3-thienyl. Thepreferences for the substituent selection and pattern of substitution onthe phenyl ring in formula V is the same as for formula II, above.

Without wishing to be bound by any theory, it is believed that thecompounds of the invention affect the MAPK signal transduction pathway,thereby affecting tumor cell growth and viability. This cell growthinhibition is associated with regulation of the ERK and JNK types ofMAPK. Without wishing to be bound by any theory, the sulfones of thepresent invention may block the phosphorylating capacity of ERK-2.

The compounds of the invention have been shown to inhibit theproliferation of tumor cells by inducing cell death. The compounds arebelieved effective against a broad range of tumor types, including butnot limited to the following: breast, prostate, ovarian, lung,colorectal, brain (i.e, glioma) and renal. The compounds are alsobelieved effective against leukemic cells. The compounds do not killnormal cells in concentrations at which tumor cells are killed.

The compounds of the invention may be administered to individuals(mammals, including animals and humans) afflicted with cancer.

The compounds are also believed useful in the treatment of non-cancerproliferative disorders, that is, proliferative disorders which arecharacterized by benign indications. Such disorders may also be known as“cytoproliferative” or “hyperproliferative” in that cells are made bythe body at an atypically elevated rate. Such disorders include, but arenot limited to, the following: hemangiomatosis in new born, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

Treatment of this broad range of tumor cells with the α,β-unsaturatedsulfone compounds of the invention leads to inhibition of cellproliferation and induction of apoptotic cell death.

Tumor cells treated with the compounds of the invention accumulate inthe G2/M phase of the cell cycle. As the cells exit the G2/M phase, theyappear to undergo apoptosis. Treatment of normal cells with the sulfonecompounds does not result in apoptosis.

The (E)-α,β, unsaturated sulfones of formula I may be prepared byKnoevenagel condensation of Q₂-aldehydes with Q₁—CH₂-sulfonyl aceticacids, according to the Scheme 1 below, wherein Q₁ and Q₂ are defined asfor formula I, above. The Q₁—CH₂-thioacetic acid B is formed by thereaction of sodium thioglycollate and a Q₁—CH₂—Cl compound A. Thethioacetic acid compound B is then oxidized with 30% hydrogen peroxideto give a corresponding sulfonyl acetic acid compound C. Condensation ofC with the aldehyde D via a Knoevenagel reaction in the presence ofbenzylamine and glacial acetic acid yields the desired(E)-α,β-unsaturated sulfone E.

The following is a more detailed two-part synthesis procedure forpreparing the formula I α,β-unsaturated sulfones, (E)-Q₁—CH₂SO₂CH═CH—Q₂,according to the above scheme.

General Procedure 1: Synthesis (E)-α,β Unsaturated Sulfones

Part A. To a solution of (8 g, 0.2 mol) sodium hydroxide in methanol(200 ml), thioglycollic acid (0.1 mol) is added slowly and theprecipitate formed is dissolved by stirring the contents of the flask.Then a compound Q₁—CH₂—Cl (0.1 mol) is added stepwise and the reactionmixture is refluxed for 2-3 hours. The cooled contents are poured ontocrushed ice and neutralized with dilute hydrochloric acid (200 ml). Theresulting corresponding thioacetic acid compound Q₁—CH₂SCH₂COOH (0.1mol) is subjected to oxidation with 30% hydrogen peroxide (0.12 mol) inglacial acetic acid (125 ml) by refluxing for 1 hour. The contents arecooled and poured onto crushed ice. The separated solid is recrystalizedfrom hot water to give the corresponding pure sulfonylacetic acidQ₁—CH₂SO₂CH₂COOH.

Part B. A mixture of the sulfonyl acetic acid compound (10 mmol), analdehyde Q₂—CHO (10 mmol), and benzylamine (200 ml) in glacial aceticacid (12 ml) is refluxed for 2-3 hours. The contents are cooled andtreated with cold ether (50 ml). Any product precipitated out isseparated by filtration. The filtrate is diluted with more ether andwashed successively with a saturated solution of sodium bicarbonate (20ml), sodium bisulfite (20 ml), dilute hydrochloric acid (20 ml) andfinally with water (35 ml). Evaporation of the dried ethereal layeryields the desired α,β-unsaturated sulfone (E)-Q₁—CH₂SO₂CH═CH—Q₂ as asolid material.

According to an alternative to Part A, the appropriate sulfonylaceticacids may be generated by substituting a thioglycollate HSCH₂COOR forthioglycollic acid, where R is an alkyl group, typically C1-C6 alkyl.This leads to the formation of the alkylthioacetate intermediate (F),

Q₁—CH₂SCH₂COOR

F

which is then converted to the corresponding thioacetic acid B byalkaline or acid hydrolysis.

The (Z)-α,β-unsaturated sulfones are prepared by the nucleophilicaddition of the appropriate thiols to optionally substitutedphenylacetylene with subsequent oxidation of the resulting sulfide byhydrogen peroxide. The procedure is analogous to the procedure generallydescribed by Reddy et al., Sulfur Letters 13:83-90(1991)for theproduction of (Z)-styryl benzylsulfones, the entire disclosure of whichis incorporated herein by reference.

In the first step of the (Z)-α,β-unsaturated sulfone synthesis, thesodium salt of an optionally mono- or di-substituted heterocyclicmercaptan of formula VI

is allowed to react with phenylacetylene or the appropriate substitutedphenylacetylene forming the pure Z-isomer of the corresponding(Z)-α,β-unsaturated sulfide in good yield.

In the second step of the synthesis, the (Z)-α,β-unsaturated sulfideintermediate is oxidized to the corresponding sulfone in the pureZ-isomeric form by treatment with hydrogen peroxide.

The following is a more detailed two-part synthesis procedure forpreparing (Z)-α,β-unsaturated sulfones:

General Procedure 2: Synthesis of (Z)-α,β-unsaturated sulfones

Part A. To a refluxing methanolic solution of the sodium salt of acompound of formula VI, prepared from 460 mg (0.02 g atom) of (i)sodium, (ii) optionally mono- or di-substituted heterocyclic mercaptanof formula VI (0.02 mol) and (iii) 80 ml of absolute methanol, is addedfreshly distilled substituted or unsubstituted phenylacetylene. Themixture is refluxed for 20 hours, cooled and then poured on crushed ice.The crude product is filtered, dried and recrystalized from methanol oraqueous methanol to yield a pure (Z)-α,β-unsaturated sulfide.

Part B. An ice cold solution of the (Z)-α,β-unsaturated sulfide (3.0g)in 30 ml of glacial acetic acid is treated with 7.5 ml of 30% hydrogenperoxide. The reaction mixture is refluxed for 1 hour and then poured oncrushed ice. The separated solid is filtered, dried, and recrystalizedfrom 2-propanol to yield the pure (Z)-α,β-unsaturated sulfone. Thepurity of the compounds is ascertained by thin layer chromatography andthe geometrical configuration is assigned by analysis of infrared andnuclear magnetic resonance spectral data.

The sulfone compounds of the present invention may be derivatized with achemical group to permit conjugation to a carrier molecule, for thepurpose of raising antibodies to the sulfones. Suitable derivatizingchemistries are well-known to those skilled in the art. Preferably, thederivative comprises a carboxylic acid derivative. The carrier maycomprise any molecule sufficiently large to be capable of generating animmune response in an appropriate host animal. One such preferredcarrier is keyhole limpet haemocyanin (KLH).

The present invention is also directed to isolated optical isomers ofcompounds according to formulae I and V. Certain compounds may have oneor more chiral centers. By “isolated” means a compound which has beensubstantially purified from the corresponding optical isomer(s) of thesame formula. Preferably, the isolated isomer is at least about 80%,more preferably at least 90% pure, even more preferably at least 98%pure, most preferably at least about 99% pure, by weight. The presentinvention is meant to comprehend diastereomers as well as their racemicand resolved, enantiomerically pure forms and pharmaceuticallyacceptable salts thereof. Isolated optical isomers may be purified fromracemic mixtures by well-known chiral separation techniques. Accordingto one such method, a racemic mixture of a compound having the structureof formula I or formula V, or chiral intermediate thereof, is separatedinto 99% wt. % pure optical isomers by HPLC using a suitable chiralcolumn, such as a member of the series of DAICEL CHIRALPAK family ofcolumns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column isoperated according to the manufacturer's instructions.

The compounds of the present invention may take the form orpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts”, embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is pharmaceutically-acceptable.Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, exampleof which are formic, acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric,salicyclic, galactaric and galacturonic acid. Suitable pharmaceuticallyacceptable base addition salts of compounds of formula I includemetallic salts made from calcium, lithium, magnesium, potassium, sodiumand zinc or organic salts made from N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of these salts may be prepared byconventional means from the corresponding compound of formula I or V byreacting, for example, the appropriate acid or base with the compound offormula I or V.

The sulfones of the invention may be administered in the form of apharmaceutical composition, in combination with a pharmaceuticallyacceptable carrier. The active ingredient in such formulations maycomprise from 0.1 to 99.99 weight percent. By “pharmaceuticallyacceptable carrier” is meant any carrier, diluent or excipient which iscompatible with the other ingredients of the formulation and todeleterious to the recipient.

The compounds of the invention may be administered to individuals(mammals, including animals and humans) afflicted with cancer.

The compounds are also useful in the treatment of non-cancerproliferative disorders, that is, proliferative disorders which arecharacterized by benign indications. Such disorders may also be known as“cytoproliferative” or “hyperproliferative” in that cells are made bythe body at an atypically elevated rate. Such disorders include, but arenot limited to, the following: hemangiomatosis in new born, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

The compounds may be administered by any route, including oral andparenteral administration. Parenteral administration includes, forexample, intravenous, intramuscular, intraarterial, intraperitoneal,intranasal, rectal, intravaginal, intravesical (e.g., to the bladder),intradermal, topical or subcutaneous administration. Also contemplatedwithin the scope of the invention is the instillation of drug in thebody of the patient in a controlled formulation, with systemic or localrelease of the drug to occur at a later time. For example, the drug maylocalized in a depot for controlled release to the circulation, or forrelease to a local site of tumor growth.

The active agent is preferably administered with a pharmaceuticallyacceptable carrier selected on the basis of the selected route ofadministration and standard pharmaceutical practice. The active agentmay be formulated into dosage forms according to standard practices inthe field of pharmaceutical preparations. See Alphonso Gennaro, ed.,Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack PublishingCo., Easton, Pa. Suitable dosage forms may comprise, for example,tablets, capsules, solutions, parenteral solutions, troches,suppositories, or suspensions.

For parenteral administration, the active agent may be mixed with asuitable carrier or diluent such as water, an oil (particularly avegetable oil), ethanol, saline solution, aqueous dextrose (glucose) andrelated sugar solutions, glycerol, or a glycol such as propylene glycolor polyethylene glycol. Solutions for parenteral administrationpreferably contain a water soluble salt of the active agent. Stabilizingagents, antioxidizing agents and preservatives may also be added.Suitable antioxidizing agents include sulfite, ascorbic acid, citricacid and its salts, and sodium EDTA. Suitable preservatives includebenzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol. Thecomposition for parenteral administration may take the form of anaqueous or nonaqueous solution, dispersion, suspension or emulsion.

For oral administration, the active agent may be combined with one ormore solid inactive ingredients for the preparation of tablets,capsules, pills, powders, granules or other suitable oral dosage forms.For example, the active agent may be combined with at least oneexcipient such as fillers, binders, humectants, disintegrating agents,solution retarders, absorption accelerators, wetting agents absorbentsor lubricating agents. According to one tablet embodiment, the activeagent may be combined with carboxymethylcellulose calcium, magnesiumstearate, mannitol and starch, and then formed into tablets byconventional tableting methods.

The specific dose of compound according to the invention to obtaintherapeutic benefit will, of course, be determined by the particularcircumstances of the individual patient including, the size, weight, ageand sex of the patient, the nature and stage of the disease, theaggressiveness of the disease, and the route of administration. Forexample, a daily dosage of from about 0.05 to about 50 mg/kg/day may beutilized. Higher or lower doses are also contemplated.

The practice of the invention is illustrated by the followingnon-limiting examples. In each of the following examples, the sulfonylacetic acid compound Q₁CH₂SO₂CH₂COOH was made according to Part A ofGeneral Procedure 1: Synthesis (E)-α,β Unsaturated Sulfones, above. Thefinal sulfone compound (E)-Q₁—CH₂SO₂CH═CH—Q₂ was recrystalized from2-propanol and the purity was checked by thin layer chromatography.Compounds containing the 3-thienyl-1,1-dioxide group were generated byoxidizing the corresponding 3-thienyl sulfone.

EXAMPLE 1 (E)-2-pyridineethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and2-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 110-111° C., was obtained in54% yield.

EXAMPLE 2 (E)-3-pyridineethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and3-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 155-156° C., was obtained in60% yield.

EXAMPLE 3 (E)-4-pyridineethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and4-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound was obtained in 52% yield.

EXAMPLE 4 (E)-2-pyridineethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 117-119° C., was obtained in53% yield.

EXAMPLE 5 (E)-3-pyridineethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and3-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 167-169° C., was obtained in51 % yield.

EXAMPLE 6 (E)-4-pyridineethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and4-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 107-109° C., was obtained in53% yield.

EXAMPLE 7 (E)-2-pyridineethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and2-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 143-145° C., was obtained in52% yield.

EXAMPLE 8 (E)-3-pyridineethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and3-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 161-162° C., was obtained in59% yield.

EXAMPLE 9 (E)-4-pyridineethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and4-pyridinecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 158-160° C., was obtained in54% yield.

EXAMPLE 10 (E)-2-thiopheneethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and2-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 146-148° C., was obtainedin 53% yield.

EXAMPLE 11 (E)-2-thiopheneethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 158-159° C., was obtainedin 56% yield.

EXAMPLE 12 (E)-2-thiopheneethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and2-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 169-170° C., was obtainedin 54% yield.

EXAMPLE 13 (E)-4-bromo-2-thiopheneethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and4-bromo-2-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 155-157° C., wasobtained in 54% yield.

EXAMPLE 14 (E)-4-bromo-2-thiopheneethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and4-bromo-2-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 150-151° C., wasobtained in 53% yield.

EXAMPLE 15 (E)4-bromo-2-thiopheneethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and4-bromo-2-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 154-155° C., wasobtained in 54% yield.

EXAMPLE 16 (E)-5-bromo-2-thiopheneethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and5-bromo-2-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 161-162° C., wasobtained in 55% yield.

EXAMPLE 17 (E)-5-bromo-2-thiopheneethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and5-bromo-2-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 190-192° C., wasobtained in 50% yield.

EXAMPLE 18 (E)-5-bromo-2-thiopheneethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and5-bromo-2-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 199-202° C., wasobtained in 52% yield.

EXAMPLE 19 (E)-2-thiophene-1,1-dioxoethenyl-4-fluorobenzyl Sulfone

A solution of the compound of Example 10 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g). The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 126-128° C., was obtained in 52% yield.

EXAMPLE 20 (E)-2-thiophene-1,1-dioxoethenyl-4-chlorobenzyl Sulfone

A solution of the compound of Example 11 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g). The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 108-110° C., was obtained in 55% yield.

EXAMPLE 21 (E)-2-thiophene-1,1-dioxoethenyl-4-bromobenzyl Sulfone

A solution of compound 12 (500 mg) in glacial acetic acid (10 ml) and30% hydrogen peroxide (1 ml) was refluxed for 1 hour and the cooledcontents were poured onto crushed ice (100 g). The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 145-147° C., was obtained in 56% yield.

EXAMPLE 22 (E)-3-thiopheneethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 159-161° C., was obtainedin 53% yield.

EXAMPLE 23 (E)-3-thiopheneethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 169-170° C., was obtainedin 59% yield.

EXAMPLE 24 (E)-3-thiopheneethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 175-177° C., was obtainedin 70% yield.

EXAMPLE 25 (E)-3-thiopheneethenyl-4-iodobenzyl Sulfone

A solution of 4-iodobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 177-179° C., was obtainedin 52% yield.

EXAMPLE 26 (E)-3-thiopheneethenyl-4-methylbenzyl Sulfone

A solution of 4-methylbenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 135-136° C., was obtainedin 55% yield.

EXAMPLE 27 (E)-3-thiopheneethenyl-4-methoxybenzyl Sulfone

A solution of 4-methoxybenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 130-131° C., was obtainedin 55% yield.

EXAMPLE 28 (E)-3-thiopheneethenyl-4-trifloromethoxylbenzyl Sulfone

A solution of 4-trifluoromethoxybenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 201-202° C., was obtainedin 52% yield.

EXAMPLE 29 (E)-3-thiopheneethenyl-2,4-dichlorobenzyl Sulfone

A solution of 2,4-dichlorobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 125-126° C., was obtainedin 53% yield.

EXAMPLE 30 (E)-3-thiopheneethenyl-3,4-dichlorobenzyl Sulfone

A solution of 3,4-dichlorobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 152-153° C., was obtainedin 51% yield.

EXAMPLE 31 (E)-3-thiopheneethenyl-4-cyanobenzyl Sulfone

A solution of 4-cyanobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 168-170° C., was obtainedin 54% yield.

EXAMPLE 32 (E)-3-thiopheneethenyl-4-nitrobenzyl Sulfone

A solution of 4-nitrobenzylsulfonylacetic acid (10 mmol) and3-thiophenecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 203-205° C., was obtainedin 54% yield.

EXAMPLE 33 (E)-3-thiophene-1,1-dioxoethenyl-4-fluorobenzyl Sulfone

A solution of the compound of Example 22 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g). The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 95-99° C., was obtained in 52% yield.

EXAMPLE 34 (E)-3-thiophene-1,1-dioxoethenyl-4-chlorobenzyl Sulfone

A solution of the compound of Example 23 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g. The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 115-120° C., was obtained in 51% yield.

EXAMPLE 35 (E)-3-thiophene-1,1-dioxoethenyl-4-bromobenzyl Sulfone

A solution of the compound of Example 24 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g. The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 152-155° C., was obtained in 50% yield.

EXAMPLE 36 (E)-3-thiophene-1,1-dioxoethenyl-4-methoxybenzyl Sulfone

A solution of the compound of Example 27 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g. The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 92-95° C., was obtained in 54% yield.

EXAMPLE 37 (E)-3-thiophene-1,1-dioxoethenyl-2,4-dichlorobenzyl Sulfone

A solution of the compound of Example 29 (500 mg) in glacial acetic acid(10 ml) and 30% hydrogen peroxide (1 ml) was refluxed for 1 hour and thecooled contents were poured onto crushed ice (100 g. The solid materialseparated was filtered and recrystallized from 2-propanol. The titlecompound, melting point 135-139° C., was obtained in 52% yield.

EXAMPLE 38 (E)-2-furanethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and2-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 103-105° C., was obtained in53% yield.

EXAMPLE 39 (E)-2-furanethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 106-108° C., was obtained in52% yield.

EXAMPLE 40 (E)-2-furanethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and2-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 125-127° C., was obtained in52% yield.

EXAMPLE 41 (E)-3-furanethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 114-117° C., was obtained in51% yield.

EXAMPLE 42 (E)-3-furanethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 154-156° C., was obtained in50% yield.

EXAMPLE 43 (E)-3-furanethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 156-158° C., was obtained in51% yield.

EXAMPLE 44 (E)-3-furanethenyl-4-iodobenzyl Sulfone

A solution of 4-iodobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 166-170° C., was obtained in52% yield.

EXAMPLE 45 (E)-3-furanethenyl-4-methylbenzyl Sulfone

A solution of 4-methylbenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 123-126° C., was obtained in53% yield.

EXAMPLE 46 (E)-3-furanethenyl-4-methoxybenzyl Sulfone

A solution of 4-methoxybenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 117-119° C., was obtained in51% yield.

EXAMPLE 47 (E)-3-furanethenyl-4-trifluoromethylbenzyl Sulfone

A solution of 4-trifluoromethylbenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 167-169° C., was obtained in51% yield.

EXAMPLE 48 (E)-3-furanethenyl-2,4-dichlorobenzyl Sulfone

A solution of 2,4-dichlorobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 104-106° C., was obtained in53% yield.

EXAMPLE 49 (E)-3-furanethenyl-3,4-dichlorobenzyl Sulfone

A solution of 3,4-dichlorobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 131-133° C., was obtained in52% yield.

EXAMPLE 50 (E)-3-furanethenyl-4-cyanobenzyl Sulfone

A solution of 4-cyanobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 175-178° C., was obtained in53% yield.

EXAMPLE 51 (E)-3-furanethenyl-4-nitrobenzyl Sulfone

A solution of 4-nitrobenzylsulfonylacetic acid (10 mmol) and3-furancarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 210-213° C., was obtained in52% yield.

EXAMPLE 52 (E)-2-thiazoleethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-thiazolecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 133-137° C., was obtained in51% yield.

EXAMPLE 53 (E)-2-pyrrolethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-pyrrolecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound was obtained.

EXAMPLE 54 (E)-2- pyrrolethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and2-pyrrolecarboxaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound was obtained.

EXAMPLE 55 (E)-2-nitro-4-thiopheneethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-nitro-4-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 228-230° C., wasobtained in 56% yield.

EXAMPLE 56 (E)-2-nitro-4-thiopheneethenyl-4-iodobenzyl Sulfone

A solution of 4-iodobenzylsulfonylacetic acid (10 mmol) and2-nitro-4-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 177-179° C., wasobtained in 67% yield.

EXAMPLE 57 (E)-2-nitro-4-thiopheneethenyl-2,4-dichlorobenzyl Sulfone

A solution of 2,4-dichlorobenzylsulfonylacetic acid (10 mmol) and2-nitro-4-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 228-230° C., wasobtained in 64% yield.

EXAMPLE 58 (E)-2-nitro-4-thiopheneethenyl-4-methoxybenzyl Sulfone

A solution of 4-methoxybenzylsulfonylacetic acid (10 mmol) and2-nitro-4-thiophenecarboxaldehyde (10 mmol) was subjected to GeneralProcedure 1, Part B. The title compound, melting point 170-172° C., wasobtained in 56% yield.

EXAMPLE 59 (E)-1-piperazineethenyl-4-fluorobenzyl Sulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and1-piperazinecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 156-157° C., was obtainedin 50% yield.

EXAMPLE 60 (E)-1-piperazineethenyl-4-chlorobenzyl Sulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and1-piperazinecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 126-128° C., was obtainedin 50% yield.

EXAMPLE 61 (E)-1-piperazineethenyl-4-bromobenzyl Sulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and1-piperazinecarboxaldehyde (10 mmol) was subjected to General Procedure1, Part B. The title compound, melting point 128-129° C., was obtainedin 52% yield.

EXAMPLE 62 (E)-1-naphthaleneethenyl-4-fluorobenzylsulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and1-naphthaldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 148-150° C., was obtained in 55%yield.

EXAMPLE 63 (E)-2-naphthaleneethenyl-4-fluorobenzylsulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and2-naphthaldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 185-186° C., was obtained in 58%yield.

EXAMPLE 64 (E)-1-naphthaleneethenyl-4-chlorobenzylsulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and1-naphthaldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 142-143° C., was obtained in 63%yield.

EXAMPLE 65 (E)-2-naphthaleneethenyl-4-chlorobenzylsulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-naphthaldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 191-193° C., was obtained in 52%yield.

EXAMPLE 66 (E)-1-naphthaleneethenyl-4-bromobenzylsulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and1-naphthaldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 147-149° C., was obtained in 52%yield.

EXAMPLE 67 (E)-2-naphthaleneethenyl-4-bromobenzylsulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and2-naphthaldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 193-194° C., was obtained in 54%yield.

EXAMPLE 68 (E)-4-fluorostyryl-1-(naphthylmethyl)sulfone

A solution of 1-(naphthylmethyl)sulfonylacetic acid (10 mmol) and4-fluorobenzaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 142-144° C., was obtained in52% yield.

EXAMPLE 69 (E)-4-chlorostyryl-1-(naphthylmethyl)sulfone

A solution of 1-(naphthylmethyl)sulfonylacetic acid (10 mmol) and4-chlorobenzaldehyde (10 mmol) was subjected to General Procedure 1,Part B. The title compound, melting point 195-197° C., was obtained in53% yield

EXAMPLE 70 (E)-4-bromostyryl-1-(naphthylmethyl)sulfone

A solution of 1-(naphthylmethyl)sulfonylacetic acid (10 mmol) and4-bromobenzaldehyde (10 mmol) was subjected to General Procedure 1, PartB. The title compound, melting point 207-209° C., was obtained in 55%yield

EXAMPLE 71 (E)-2-nitrostyryl-1-(naphthylmethyl)sulfone

A solution of 1-(naphthylmethyl)sulfonylacetic acid (10 mmol) and2-nitrobenzaldehyde (10 mmol) was subjected to General Procedure 1, PartB. The title compound, melting point 188-192° C., was obtained in 62%yield

EXAMPLE 72 (E)-3-nitrostyryl-1-(naphthylmethyl)sulfone

A solution of 1-(naphthylmethyl)sulfonylacetic acid (10 mmol) and3-nitrobenzaldehyde (10 mmol) was subjected to General Procedure 1, PartB. The title compound, melting point 192-194° C., was obtained in 59%yield.

EXAMPLE 73 (E)-4-nitrostyryl-1-(naphthylmethyl)sulfone

A solution of 1-(naphthylmethyl)sulfonylacetic acid (10 mmol) and4-nitrobenzaldehyde (10 mmol) was subjected to General Procedure 1, PartB. The title compound, melting point 252-254° C., was obtained in 61%yield.

EXAMPLE 74 (E)-9-anthraceneethenyl-4-fluorobenzylsulfone

A solution of 4-fluorobenzylsulfonylacetic acid (10 mmol) and9-anthraldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 93-95° C., was obtained in 56% yield.

EXAMPLE 75 (E)-9-anthraceneethenyl-4-chlorobenzylsulfone

A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and9-anthraldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 122-124° C., was obtained in 53%yield.

EXAMPLE 76 (E)-9-anthraceneethenyl-4-bromobenzylsulfone

A solution of 4-bromobenzylsulfonylacetic acid (10 mmol) and9-anthraldehyde (10 mmol) was subjected to General Procedure 1, Part B.The title compound, melting point 172-175° C., was obtained in 51%yield.

Effect of Sulfones on Tumor Cell Lines

A. Cells

The effect of the sulfones on normal fibroblasts and on tumor cells ofprostate, colon, lung and breast origin was examined utilizing thefollowing cell lines: prostate tumor cell line DU-145; colorectalcarcinoma cell line DLD-1; non-small cell lung carcinoma cell line H157;and breast tumor cell line BT-20. BT-20 is an estrogen-unresponsive cellline. NIH/3T3 and HFL are normal murine and human fibroblasts,respectively. BT-20, DLD-1 and H157 were grown in Dulbecco's modifiedEagle's medium (DMEM) containing 10% fetal bovine serum supplementedwith penicillin and streptomycin. DU145 was cultured in RPMI with 10%fetal bovine serum containing penicillin and streptomycin. NIH3T3 andHFL cells were grown in DMEM containing 10% calf serum supplemented withpenicillin and streptomycin. All cell cultures were maintained at 37° C.in a humidified atmosphere of 5% CO₂.

B. Treatment with Sulfones and Viability Assay

Cells were treated with test compound at 2.5 mM concentration and cellviability was determined after 96 hours by the Trypan blue exclusionmethod. The results are set forth in Table 1. Activity for each compoundis reported as a range of cell induced death (% Death) with the lowestactivity in the range of 5-10%.

Normal cells HFL and NIH 3T3 were treated with the same compounds inTable 1 under the same conditions of concentration and time. The normalcells displayed 5% growth inhibition but no appreciable cell death. Thepercent cell death is scored in Table 1 as follows:

TABLE 1 Effect of Sulfones on Tumor cells I

Tumor Cells Ex. Q₁ Q₂ DU145 DLD-1 H157 BT20  1 4-fluorophenyl2-pyridyl + + + +  2 4-fluorophenyl 3-pyridyl + + + +  3 4-fluorophenyl4-pyridyl ND ND ND ND  4 4-chlorophenyl 2-pyridyl + + + +  54-chlorophenyl 3-pyridyl + + + +  6 4-chlorophenyl 4-pyridyl + + + +  74-bromophenyl 2-pyridyl + + + +  8 4-bromophenyl 3-pyridyl ++ ++ ++ ++ 9 4-bromophenyl 4-pyridyl + + + + 10 4-fluorophenyl 2-thienyl + + + +11 4-chlorophenyl 2-thienyl + + + + 12 4-bromophenyl 2-thienyl + + + +13 4-fluorophenyl 4-bromo-2-thienyl + + + + 14 4-chlorophenyl4-bromo-2-thienyl + + + + 15 4-bromophenyl 4-bromo-2-thienyl + + + + 164-fluorophenyl 5-bromo-2-thienyl + + + + 17 4-chlorophenyl5-bromo-2-thienyl + + + + 18 4-bromophenyl 5-bromo-2-thienyl + + + + 194-fluorophenyl 2-thienyl-1,1- ND ND ND ND dioxide 20 4-chlorophenyl2-thienyl-1,1- ND ND ND ND dioxide 21 4-bromophenyl 2-thienyl-1,1- ND NDND ND dioxide 22 4-fluorophenyl 3-thienyl + + + + 23 4-chlorophenyl3-thienyl +++ +++ +++ +++ 24 4-bromophenyl 3-thienyl +++ +++ +++ +++ 254-iodophenyl 3-thienyl ++ ++ ++ ++ 26 4-methylphenyl 3-thienyl + + + +27 4-methoxyphenyl 3-thienyl ++++ ++++ ++++ ++++ 28 4-trifluoro-3-thienyl + + + + methylphenyl 29 2,4-dichlorophenyl 3-thienyl ++++ ++++++++ ++++ 30 3,4-dichlorophenyl 3-thienyl + + + + 31 4-cyanophenyl3-thienyl + + + + 32 4-nitrophenyl 3-thienyl + + + + 33 4-fluorophenyl3-thienyl-1,1- + + + + dioxide 34 4-chlorophenyl 3-thienyl-1,1- + + + +dioxide 35 4-bromophenyl 3-thienyl-1,1- + + + + dioxide 364-methoxyphenyl 3-thienyl-1,1- + + + + dioxide 37 2,4-dichlorophenyl3-thienyl-1,1- ++ ++ ++ ++ dioxide 38 4-fluorophenyl 2-furyl ND ND ND ND39 4-chlorophenyl 2-furyl ND ND ND ND 40 4-bromophenyl 2-furyl ND ND NDND 41 4-fluorophenyl 3-furyl + + + + 42 4-chlorophenyl 3-furyl ++++++++++ +++++ +++++ 43 4-bromophenyl 3-furyl +++++ +++++ +++++ +++++ 444-iodophenyl 3-furyl +++++ +++++ +++++ +++++ 45 4-methylphenyl 3-furylND ND ND ND 46 4-methoxyphenyl 3-furyl +++++ +++++ +++++ +++++ 474-trifluoro- 3-furyl ++++ ++++ ++++ ++++ methylphenyl 482,4-dichlorophenyl 3-furyl +++++ +++++ +++++ +++++ 49 3,4-dichlorophenyl3-furyl +++++ ++++ ++++ ++++ 50 4-cyanophenyl 3-furyl + + + + 514-nitrophenyl 3-furyl + + + + 52 4-chlorophenyl 2-thiazolyl ND ND ND ND53 4-chlorophenyl 2-pyrrolyl ND ND ND ND 54 4-bromophenyl 2-pyrrolyl NDND ND ND 55 4-chlorophenyl 2-nitro-4-thienyl ++ ++++ + + 56 4-iodophenyl2-nitro-4-thienyl + + + + 57 2,4-dichlorophenyl 2-nitro-4-thienyl ++++ + + 58 4-methoxyphenyl 2-nitro-4-thienyl ++++ +++++ +++++ +++ 594-fluorophenyl 1-piperazinyl ND ND ND ND 60 4-chlorophenyl 1-piperazinylND ND ND ND 61 4-bromophenyl 1-piperazinyl ND ND ND ND 62 4-fluorophenyl1-naphthyl + + + + 63 4-fluorophenyl 2-naphthyl + + + + 644-chlorophenyl 1-naphthyl ++ ++ ++ ++ 65 4-chlorophenyl2-naphthyl + + + + 66 4-bromophenyl 1-naphthyl ++ ++ ++ ++ 674-bromophenyl 2-naphthyl + + + + 68 1-naphthyl 4-fluorophenyl + + + + 691-naphthyl 4-chlorophenyl + + + + 70 1-naphthyl 4-bromophenyl + + + + 711-naphthyl 2-nitrophenyl +++ ND ND +++ 72 1-naphthyl 3-nitrophenyl + NDND + 73 1-naphthyl 4-nitrophenyl + + ++ + 74 4-fluorophenyl 9-anthryl+++ ++++ +++++ ++++ 75 4-chlorophenyl 9-anthryl ND ND ND ND 764-bromophenyl 9-anthryl ++++ +++ +++ ++++ (−) = 0% (+) = 5-10% (++) =10-15% (+++) = 40-50% (++++) = 50-60% (+++++) = >80% ND = not done.

All references cited herein are incorporated by reference. The presentinvention may be embodied in other specific forms without departing fromthe spirit or essential attributes thereof and, accordingly, referenceshould be made to the appended claims, rather than to the foregoingspecification, as indication the scope of the invention.

What is claimed is:
 1. (amended) A compound of the formula I:

wherein: Q₁ is selected from the group consisting of (a) a phenylradical according to formula II

wherein R₁, R₂, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1 -C6 trifluoroalkoxy andtrifluoromethyl; R₃ is selected from the group consisting of halogen, C1-C6 alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6trifluoroalkoxy and trifluoromethyl; (b) an aromatic radical selectedfrom the group consisting of 1-naphthyl, 2- naphthyl and 9-anthryl; and(c) an aromatic radical according to formula III

wherein n₁ is 1 or 2, Y₁ and Y₂ are independently selected from thegroup consisting of hydrogen and halogen and X₁ is selected from thegroup consisting of oxygen, nitrogen, sulfur and

Q₂ is selected from the group consisting of (d) a phenyl radicalaccording to formula II

wherein R₁, R₂, R₁ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl; R₃ is selected from the group consisting of halogen,C1-C6 alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6trifluoroalkoxy and trifluoromethyl; (e) an aromatic radical selectedfrom the group consisting of 1-naphthyl, 2- naphthyl and 9-anthryl; (f)an aromatic radical according to formula IV

wherein n₂ is 1 or 2, Y₃ and Y₄ are independently selected from thegroup consisting of hydrogen, halogen, and nitro, and X₂, X₃ and X₄ areindependently selected from the group consisting of carbon, oxygen,nitrogen, sulfur and

provided that not all of X₂, X₃ and X₄ may be carbon; and (g)1-piperazinyl; provided that at least one of Q₁ or Q₂ is other than aphenyl radical according to formula II; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 wherein Q₁ is a phenylradical according to formula II

wherein R₁, R₂, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl. C1 -C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1 -C6 trifluoroalkoxy andtrifluoromethyl; R₃ is selected from the group consisting of halogen,C1-C6 alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6trifluoroalkoxy and trifluoromethyl; or a pharmaceutically acceptablesalt thereof.
 3. A compound according to claim 2 wherein R₁, R₂, R₄ andR₅ are independently selected from the group consisting of hydrogen,halogen, C₁-C₃ alkoxy and trifluoromethyl, and R₃ is selected from thegroup consisting of halogen, C₁-C6 alkoxy and trifluoromethyl.
 4. Thecompound according to claim 3 which is(E)-3-furanethenyl-3,4-dichlorobenzyl sulfone.
 5. A compound accordingto claim 3 wherein R₁ is hydrogen or halogen; and R₂, R₄ and R₅ arehydrogen.
 6. A compound according to claim 5 wherein Q₂ is selected fromthe group consisting of 3-furyl, 3-thienyl, 3-thienyl-1-dioxide,2-nitro-4-thienyl, 9-anthryl, 1-naphthyl and 2-naphthyl.
 7. The compoundaccording to claim 5 which is (E)-3-thiopheneethenyl-4-chlorobenzylsulfone.
 8. The compound according to claim 5 which is(E)-3-thiopheneethenyl-4-bromobenzyl sulfone.
 9. The compound accordingto claim 5 which is (E)-3-thiopheneethenyl-4-methoxybenzyl sulfone. 10.The compound according to claim 5 which is(E)-3-thiopheneethenyl-2,4-dichlorobenzyl sulfone.
 11. The compoundaccording to claim 5 which is(E)-3-thiophene-1,1-dioxoethenyl-2,4-dichlorobenzyl sulfone.
 12. Thecompound according to claim 5 which is (E)-3-furanethenyl-4-chlorobenzylsulfone.
 13. The compound according to claim 5 which is(E)-3-furanethenyl-4-bromobenzyl sulfone.
 14. The compound according toclaim 5 which is (E)-3-furanethenyl-4-iodobenzyl sulfone.
 15. Thecompound according to claim 5 which is(E)-3-furanethenyl-4-methoxybenzyl sulfone.
 16. The compound accordingto claim 5 which is (E)-3-furanethenyl-4-trifluoromethylbenzyl sulfone.17. The compound according to claim 5 which is(E)-3-furanethenyl-2,4-dichlorobenzyl sulfone.
 18. The compoundaccording to claim 5 which is(E)-2-nitro-4-thiopheneethenyl-4-chlorobenzyl sulfone.
 19. The compoundaccording to claim 5 which is(E)-2-nitro-4-thiopheneethenyl-4-methoxybenzyl sulfone.
 20. The compoundaccording to claim 5 which is(E)-9-anthraceneethenyl-4-fluorobenzylsulfone.
 21. The compoundaccording to claim 5 which is(E)-9-anthraceneethenyl-4-chlorobenzylsulfone.
 22. The compoundaccording to claim 5 which is(E)-9-anthraceneethenyl-4-bromobenzylsulfone.
 23. A compound accordingto claim 1 wherein Q₁ is 1-naphthyl or 2-naphthyl and Q₂ is a phenylradical according to formula II

wherein: R₁, R₂, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl; R₃ is selected from the group consisting of halogen,C1-C6 alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6trifluoroalkoxy and trifluoromethyl; or a pharmaceutically acceptablesalt thereof.
 24. A compound selected from the group consisting of(E)-2-nitrostyryl-1- (naphthylmethyl)sulfone,(E)-3-nitrostyryl-1-(naphthylmethyl)sulfone and (E)-4-nitrostyryl-1-(naphthylmethyl)sulfone.
 25. A compound of the formula V:

wherein: X is sulfur or oxygen; Y_(a) and Y_(b) are independentlyselected from the group consisting of hydrogen, halogen, and nitro; andR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of halogen, C1—C6 alkyl, C1—C6 alkoxy, nitro, cyano,carboxyl, hydroxyl, amino, C1—C6 trifluoroalkoxy and trifluoromethyl; ora pharmaceutically acceptable salt thereof.
 26. An isolated opticalisomer of a compound according to claim 1, or pharmaceuticallyacceptable salt thereof.
 27. An isolated optical isomer of a compoundaccording to claim 25, or pharmaceutically acceptable salt thereof. 28.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of the formula V:

wherein: X is sulfur or oxygen; Y_(a) and Y_(b) are independentlyselected from the group consisting of hydrogen, halogen, and nitro; andR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano.carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy and trifluoromethyl; ora pharmaceutically acceptable salt thereof.
 29. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound according to formula I:

wherein: Q₁ is selected from the group consisting of (a) a phenylradical according to formula II

wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl; (b) an aromatic radical selected from the groupconsisting of 1-naphthyl, 2- naphthyl and 9-anthryl; and (c) an aromaticradical according to formula III

wherein n₁ is 1 or 2, Y₁ and Y₂ are independently selected from thegroup consisting of hydrogen, halogen, and nitro, and X₁ is selectedfrom the group consisting of oxygen, nitrogen, sulfur and

Q₂ is selected from the group consisting of (d) a phenyl radicalaccording to formula II

wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl; (e) an aromatic radical selected from the groupconsisting of 1-naphthyl, 2- naphthyl and 9-anthryl; (f) an aromaticradical according to formula IV

wherein n₂ is 1 or 2, Y₃ and Y₄ are independently selected from thegroup consisting of hydrogen, halogen, and nitro, and X₂, X₃ and X₄ areindependently selected from the group consisting of carbon, oxygen,nitrogen, sulfur and

provided that not all of X₂, X₃ and X₄ may be carbon; and (g)1-piperazinyl; provided that at least one of Q₁ or Q₂ is other than aphenyl radical according to formula II; or a pharmaceutically acceptablesalt thereof.
 30. A method of treating an individual for a proliferativedisorder comprising administering to said individual an effective amountof a pharmaceutical composition according to claim 29 or
 28. 31. Amethod according to claim 30 wherein the proliferative disorder isselected from the group consisting of hemangiomatosis in new born,secondary progressive multiple sclerosis, chronic progressivemyelodegenerative disease, neurofibromatosis, ganglioneuromatosis,keloid formation, Pagets Disease of the bone, fibrocystic disease of thebreast, Peronies and Duputren's fibrosis, restenosis and cirrhosis. 32.A method according to claim 30 wherein the proliferative disorder iscancer.
 33. A method according to claim 32 wherein the cancer isselected from the group consisting of ovarian, breast, prostate, lung,renal, colorectal and brain cancers, or the cancer is a leukemia.
 34. Amethod of inducing apoptosis of tumor cells in an individual afflictedwith cancer comprising administering to said individual an effectiveamount of a pharmaceutical composition according to c1aim 29 or
 28. 35.A method according to claim 28 wherein the tumor cells are selected fromthe group consisting of ovarian, breast, prostate, lung, colorectal,renal and brain tumors.
 36. A process for preparing a compound of claim1 comprising condensing a compound of formula Ia

with a compound of the formula

wherein: Q₁ is selected from the group consisting of (a) a phenylradical according to formula II

wherein R₁, R₂, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl; R₃ is selected from the group consisting of halogen,C1-C6 alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6trifluoroalkoxy and trifluoromethyl; (b) an aromatic radical selectedfrom the group consisting of 1-naphthyl, 2- naphthyl and 9-anthryl; and(c) an aromatic radical according to formula III

wherein n₁ is 1 or 2, Y₁ and Y₂ are independently selected from thegroup consisting of hydrogen and halogen and X₁ is selected from thegroup consisting of oxygen, nitrogen, sulfur and

Q₂ is selected from the group consisting of (d) a phenyl radicalaccording to formula II

wherein R₁, R₂, R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro,cyano, carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy andtrifluoromethyl; R₃ is selected from the group consisting of halogen,C1-C6 alkoxy, nitro, cyano, carboxyl, hydroxyl, amino, C1-C6trifluoroalkoxy and trifluoromethyl; (e) an aromatic radical selectedfrom the group consisting of 1-naphthyl, 2- naphthyl and 9-anthryl; (f)an aromatic radical according to formula IV

wherein n₂ is 1 or 2, Y₃ and Y₄ are independently selected from thegroup consisting of hydrogen, halogen, and nitro, and X₂, X₃ and X₄independently selected from the group consisting of carbon, oxygen,nitrogen, sulfur and

provided that not all of X₂, X₃ and X₄ maybe carbon; and (g)1-piperazinyl; provided that at least one of Q₁ or Q₂ is other than aphenyl radical according to formula II.
 37. A process according to claim36 wherein the formula Ia compound is prepared by reacting sodiumglycollate with a compound of the formula Q₁CH₂Cl to form a thioaceticcompound of the formula

which is then oxidized to form a compound of formula Ia.
 38. A processaccording to claim 36 wherein the thioacetic acid compound Q₁CH₂SCH₂COOHis prepared by reacting a compound of the formula HSCH₂COOR, where R isC1-C6 alkyl, with a compound of the formula Q₁CH₂Cl to form anintermediate of the formula:

and hydrolyzing said intermediate to obtain said thioacetic acidcompound Q₁CH₂SCH₂COOH.
 39. A process for preparing a compound of claim25 comprising reacting a compound of the formula

with a compound of the formula

to form a sulfide compound of formula Va:

and oxidizing said formula Va compound to form a compound according toclaim 25, wherein: X is sulfur or oxygen; Y_(a) and Y_(b) areindependently selected from the group consisting of hydrogen, halogen,and nitro; and R₁, R₂, R₃, R₄ and R₅ are independently selected from thegroup consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano,carboxyl, hydroxyl, amino, C1-C6 trifluoroalkoxy and trifluoromethyl.40. A method according to claim 33 wherein the cancer is selected fromthe group consisting of breast, prostate, non-small cell lung andcolorectal cancers.
 41. A method according to claim 35 wherein the tumorcells are selected from the group consisting of breast, prostate,non-small cell lung and colorectal tumors.